Patent EA-002620-B1 (EA)
Title: New 1-aza-2-alkyl-6-aryl-cycloalcane compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: RAULT SYLVAIN
IPC: C07D223/08
Filed: 2000-04-27
Abstract: 1. A compound selected from those of formula (I):   wherein: n represents 0 or 1, R1 represents hydrogen, aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)acyl, linear or branched (C1-C6)alkoxycarbonyl, aryl-(C1-C6)alkoxycarbonyl in which the alkoxy moiety is linear or branched, or trifluoroacetyl, R2 represents linear or branched (C1-C6)alkyl, X represents oxygen, chlorine, OR3, SR4 or NOR5, wherein R3 represents hydrogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)acyl, linear or branched (C1-C6)alkoxycarbonyl, or aryl-( C1-C6)alkoxycarbonyl in which the alkoxy moiety is linear or branched, R4 represents hydrogen, linear or branched (C1-C6)alkyl, or aryl, R5 represents hydrogen or linear or branched (C1-C6)alkyl optionally substituted by one or more identical or different groups selected from hydroxy, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), and linear or branched (C1-C6)alkoxy, --- represents a single or double bond, it being understood that the valency of the atoms is respected, Ar represents aryl or heteroaryl, its isomers and addition salts thereof with a pharmaceutically-acceptable acid, with the proviso that the compound of formula (I) is other than: 6-methyl-2-phenyl-2,3-dihydro-4-pyridinone, 2-methyl-6-phenyl-4-piperidinone, N-benzyl-2-(R'2)-6-phenyl-4-piperidinones wherein R<'>2 represents a methyl, ethyl, propyl, or isopropyl group, and 2-(R"2)-6-phenyl-4-piperidinols wherein R"2 represents an isopropyl or butyl group, on the understanding that the term "aryl" means phenyl, biphenylyl, naphthyl, or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, trihalomethyl, and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), and that the term "heteroaryl" denotes an aromatic, mono- or bi-cyclic, 5- to 12-membered group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl group may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, trihalomethyl, and amino (optionally substituted by one ore more linear or branched (C1-C6)alkyl groups). 2. Compound of claim 1, in which n represents 0. 3. Compound of claim 1, in which X represents oxygen or OR3 wherein R3 is as defined in claim 1. 4. Compound of claim 1, in which X represents NOR5 wherein R5 is as defined in claim 1. 5. Compound of claim 1, in which X represents SR4 wherein R4 is as defined in claim 1. 6. Compound of claim 1, in which X represents chlorine. 7. Compound of claim 3, in which X represents oxygen or OR3 wherein R3 represents hydrogen. 8. Compound of any claims 1 to 7, in which R1 represents hydrogen. 9. Compound of any claims 1 to 8, in which Ar represents optionally substituted phenyl. 10. Compound of any claims 1 to 8, in which Ar represents optionally substituted thienyl. 11. Compound of any claims 1 to 8, in which Ar represents optionally substituted pyridyl. 12. Compound of claim 1 which is (+-)-2-(3-chlorophenyl)-6-methyl-2,3-dihydro-4(1H)-pyridinone, its isomers and addition salts thereof with a pharmaceutically-acceptable acid. 13. Compound of claim 1 which is (2R*,4S*,6R*)-2-phenyl-6-methyl-4-piperidinol, its isomers and addition salts thereof with a pharmaceutically-acceptable acid. 14. Process for the preparation of compounds of formula (I), characterised in that a compound of formula (II):   wherein Ar and n are as defined for formula (I), is reacted with thionyl chloride to yield the corresponding acid chloride, which is reacted with a compound of formula (III):   wherein R2 is as defined for formula (I), in the presence of samarium triiodide, to yield, after deprotection by an acid HA, the compound of formula (IV):   wherein Ar, n and Rs are as defined hereinbefore and HA represents a proton donor acid, which compound of formula (IV) is then reacted in a basic medium to yield the compound of formula (la), a particular case of the compounds of formula (I):   wherein Ar, n and R2 are as defined hereinbefore, which compound of formula (la) is condensed, if desired, with a compound of formula R'1-Y, wherein R'1 represents an aryl-( C1-C6)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a linear or branched (C1-C6)alkoxycarbonyl group, an aryl-(C1-C6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched, or a trifluoroacetyl group and Y represents a leaving group, to yield the compound of formula (Ib), a particular case of the compounds of formula (I):   wherein Ar, n, R'1 and R2 are as defined hereinbefore, which compound of formula (la) or (Ib) is converted, if desired, either by partial reduction with the aid of an appropriate reducing agent, followed, if desired, by alkylation, acylation or esterification of the hydroxy function to yield the compound of formula (Ic), a particular case of the compounds of formula (I) :   wherein Ar, n and R2 are as defined hereinbefore and R1 and R3 are as defined for formula (I), - or by complete reduction with the aid of an appropriate reducing agent to yield the compound of formula (Id), a particular case of the compounds of formula (I) :   wherein Ar, n, R1 and R2 are as defined hereinbefore, which compound of formula (Id) is reacted, if desired, either with a compound of formula R'3-Y, wherein R'3 represents a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a linear or branched (C1-C6)alkoxycarbonyl group or an aryl-(C1-C6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched and Y represents a leaving group, to yield the compound of formula (le), a particular case of the compounds of formula (I):   wherein Ar, n, R1, R2 and R'3 are as defined hereinbefore, or in an oxidation reaction using an appropriate oxidising agent, to form an oxo group, yielding the compound of formula (If), a particular case of the compounds of formula (I):   wherein Ar, n, R1 and R2 are as defined hereinbefore, which compounds of formula (la), (Ib) or (If) are reacted, if desired, - either with a chlorinating agent such as, for example, thionyl chloride to yield the compound of formula (Ig), a particular case of the compounds of formula (I) :   wherein Ar, n, R1 and R2 are as defined hereinbefore and --- is as defined for formula (I), which is reacted, if desired, with a compound of formula HSR4, wherein R4 is as defined for formula (I), to yield the compound of formula (Ih), a particular case of the compounds of formula (I) :   wherein Ar, n, R1, R2, R4 and --- are as defined for formula (I), - or with a compound of formula H2N-OR5, wherein R5 is as defined for formula (I), to yield the compound of formula (li), a particular case of the compounds of formula (I) :   wherein Ar, n, R1, R2, R5 and --- are as defined hereinbefore, the compounds of formulae (I/a), (Ib), (Ic), (Id), (le), (If), (Ig), (Ih) and (li) constituting the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their isomers according to a conventional separation technique and are converted, if desired, into their addition salts with a pharmaceutically acceptable acid. 15. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 13, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable carriers. 16. Pharmaceutical composition according to claim 15 for use as a facilitator of memory and cognition. 17. Pharmaceutical composition according to claim 15 for use as an antalgic agent.